DIMERIZATION OF THE MUSCLE-SPECIFIC KINASE INDUCES TYROSINE PHOSPHORYLATION OF ACETYLCHOLINE-RECEPTORS AND THEIR AGGREGATION ON THE SURFACEOF MYOTUBES

During development of the neuromuscular junction, neuronal splice vari ants of agrin initiate the aggregation of acetylcholine receptors on t he myotube surface. The muscle-specific kinase is thought to be part o f an agrin receptor complex, although the recombinant protein does not bind agrin with high affinity. To specify its function, we induced ph osphorylation and activation of this kinase in the absence of agrin by incubating myotubes with antibodies directed against its N-terminal s equence, Antibody-induced dimerization of the muscle-specific kinase b ut not treatment with Fab fragments was sufficient to trigger two key events of early postsynaptic development: acetylcholine receptors accu mulated into aggregates, and their P-subunits became phosphorylated on tyrosine residues. Heparin partially inhibited receptor aggregation i nduced by both agrin and anti-muscle-specific kinase antibodies, In co ntrast, it did not affect kinase or acetylcholine receptor phosphoryla tion. These data indicate that agrin induces postsynaptic differentiat ion by dimerizing the muscle-specific kinase, They also suggest that a ctivation of the kinase domain can account for only part of agrin's ef fects. Dimerization of this molecule appears to activate an additional signal, mast likely by organizing a scaffold for other postsynaptic p roteins.